Compounds for inhibiting KSP kinesin activity

A compound having the general structure shown in Formula (I), or a pharmaceutically acceptable salt, or an ester thereof:

• wherein X, R1, R2, R3, p, E, ring A, and ring B are selected independently of each other and wherein:
• p is 0, 1, 2, 3, or 4;
• X is S;
• ring A (including E and the unsaturation shown) is a 4-7 membered cycloalkenyl ring and E is —C(R4)(R5)—;
• or
• ring A (including E and the unsaturation shown) is a 5-6 membered heterocycloalkylenyl ring and E is selected from the group consisting of —O—, —S—, —S(O)—, —S(O)2—, and —N(R6)—;
• ring B is a 5-6 membered aromatic ring optionally substituted with halogen;
• R1 is phenyl optionally substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, —OH, —CN, —NO2, haloalkyl, and —NR21R22;
• R2 is selected from the group consisting of —C(Z)R7,—C(Z)NR9R10, and —C(Z)OR8,
• wherein each Z is independently selected from the group consisting of (═O), (═S), (═N(R13)), (═N(CN)), (═N(OR14)), (═N(R15)(R16)), and (═C(R17)(R18));
• each R3 (when present) is independently selected from the group consisting of alkyl, alkenyl, —CN, —NO2, —C(O)R24, —C(S)R24, and —C(O)OR20,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, —CN, —NO2, alkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, —C(O)R24,
• or, alternatively, when p is 2, 3, or 4, any two R3 groups bound to the same ring carbon atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, or a spiroheterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of —NH—, —NR6—, —S—, —S(O)—, —S(O)2—, and —O—, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of —NH—, —NR6—, —S—, —S(O)—, —S(O)2—, and —O—,
• or, alternatively, R2 and R3, together with the atom to which they are attached, are taken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of —NH—, —NR6—, —S—, —S(O)—, —S(O)2—, and —O—, or a heterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of —NH—, —NR6—, —S—, —S(O)—, —S(O)2—, and —O—;
• each R4 (when not joined with R5) is independently selected from the group consisting of H and alkyl;
• each R5 (when not joined with R4) is independently selected from the group consisting of H and alkyl;
• or, alternatively, R4 and R5, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, —OR19, —NR21R22,and —C(O)R24;
• each R6 is independently selected from the group consisting of H, alkyl, and —C(O)R24
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22,and —C(O)R24;
• each R7 is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R8 is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R9 (when not joined with R10) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R10 (when not joined with R9) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• or, alternatively, R9 and R10, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R13 is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R14 is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, and —C(O)R24;
• each R15 (when not joined with R16) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R16 (when not joined with R15) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• or, alternatively, R15 and R16, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R17 (when not joined with R18) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R18 (when not joined with R17) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• or, alternatively, R17 and R18, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S,
• wherein each is optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, —OR19, —NR21R22, and —C(O)R24;
• each R19 is independently selected from the group consisting of H and alkyl;
• each R20 is independently selected from the group consisting of H and alkyl;
• each R21 (when not joined with R22) is independently selected from the group consisting of H and alkyl;
• each R22 (when not joined with R21) is independently selected from the group consisting of H and alkyl;
• and
• each R24 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl.